INTRODUCTION
Since 1960 the efforts of the United States to reduce the health impact of influenza have been based on recommendations to annually vaccinate target groups. Because of the higher risk of serious complications or death from influenza virus infection, 1, 2 the primary target groups were those ≥6 months of age with certain chronic conditions and everyone ≥65 years of age. Vaccination has also been recommended for those in close contact with high risk persons to reduce transmission of influenza from household members and health care workers to high risk persons.
In 2000 the Advisory Committee on Immunization Practices (ACIP; the federal advisory group that advises the Centers for Disease Control and Prevention and the Department of Health and Human Services on vaccination practices) recommended annual influenza vaccination of people ≥50 years because certain chronic conditions are more prevalent among persons 50 to 64 years. 3 In 2002 the ACIP also began to encourage vaccination of healthy children 6 to 23 months of age, when feasible. This was based on studies showing that young children are more likely to have an influenza-related hospital admission. 4 However, the ACIP stopped short of making a full recommendation for universal influenza vaccination of children because of certain outstanding issues. Table 1 summarizes the groups currently targeted for annual vaccination. 2
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TABLE 1: Current ACIP influenza vaccination recommendations
THE BURDEN OF INFLUENZA IN CHILDREN
US community and cohort studies show that influenza virus infection rates and illnesses are usually highest among children. Infection rates (sometimes >30% in young children) vary from year to year, depending on factors such as the predominant circulating influenza type/subtype and strain and immunity to specific strains. The highest rates of infection are generally in preschool or young school age children and decrease with age. 5–9 Most influenza-related illnesses in children are respiratory illnesses, acute otitis media and secondary bacterial infections that are treated at home or in an outpatient setting. 10, 11 Although influenza-related deaths are uncommon in this group, 12 illnesses resulting in hospital admission are common in very young children. In studies of influenza epidemics in the 1970s and 1980s, acute respiratory disease rates or “excess hospitalization” rates (i.e. rates above the expected background admission rates for periods when influenza virus circulation is low or absent) among children <5 years of age without high risk conditions were similar to admission rates for influenza among the elderly. 6, 13–16 Elderly people generally have the lowest infection rates, but the highest death rates from influenza (>90% of the estimated 36 000 annual deaths). 5, 7, 12, 17Figure 1 shows the rates of infection, hospital admission and death by age.
Fig: 1. Rates of influenza infection, hospital admission and death by age.
A, influenza infection rate per 1000 persons per year, Tecumseh, 1976 to 1980. The rates among children <5 years of age may be underestimated because of the insensitivity of serologic tests in this age group.
18 B, rate of acute respiratory hospital admission per 100 000 persons attributed to influenza for members of an HMO during the 1983 influenza A (H3N2) epidemic.
6 C, estimated annual influenza-related mortality rate per 100 000 person-years in the US for 1990 to 1991 through 1998 to 1999 seasons.
12In the late 1990s the ACIP began considering ways of expanding influenza vaccination recommendations. Given that acute respiratory disease and excess hospitalization during influenza seasons were greatest at the extremes of age, young children were one of the groups that were discussed. 6, 13–16 However, the study data reviewed by the ACIP were not adjusted for possible confounding effects of other respiratory viruses, especially respiratory syncytial virus (RSV), the most frequent viral cause of acute lower respiratory disease among infants in winter. Consequently the ACIP requested additional studies to clearly define influenza-related admission rates among children, and two studies were conducted that attempted to control for RSV circulation using different epidemiologic approaches.
Izurieta et al. 19 conducted a retrospective cohort study of healthy children (i.e. without medical conditions that increased the risk for influenza complications) and high risk children from 2 different Health Maintenance Organizations (HMOs), one in the San Francisco Bay area and one in Seattle, during 1992 through 1997. This study used local viral surveillance data to identify periods when influenza virus and RSV circulated concurrently and separately. Rates of hospital admission for acute respiratory diseases in children were estimated in periods when influenza activity predominated over RSV activity. Excess admissions were estimated using 2 different baseline periods, a periinfluenza period (the months immediately bordering the influenza period when circulation of influenza viruses is low) and a summer baseline. The most conservative estimated excess admission rates for influenza in healthy children <2 years of age were 107 and 120 per 100 000 person-months for the 2 HMOs respectively, which were equivalent to annual admission rates of 140 and 190 per 100 000 healthy children. During influenza periods the risk of hospital admission in healthy children <2 years of age was similar to the risk in 5- to 17-year-old children with high risk conditions for whom vaccination is currently recommended. The healthy young children were also ∼12 times more likely to be admitted than healthy children 5 to 17 years of age.
Although these data clearly showed that healthy young children were at increased risk for influenza-related hospital admissions, the admission rates for acute respiratory disease were 4 to 5 times higher in children of the same age who had chronic high risk conditions. This underscores the importance of continued efforts to vaccinate children of all ages with chronic medical conditions.
The second study by Neuzil et al. 10 was a retrospective cohort study of healthy children <15 years of age who were enrolled in the Tennessee Medicaid Program during 1973 through 1993. Influenza seasons were defined by using local virologic surveillance data. This study estimated annual rates for influenza-related acute cardiopulmonary admissions of 1000, 500 and 20 per 100 000 children <6 months, 6 to 11 months and 1 to 3 years, respectively. Excess admission rates attributable to influenza were calculated by subtracting periinfluenza season rates from influenza period rates. The estimates of influenza-related admission rates remained similar even after excluding periods of RSV circulation.
Although both of these studies attempted to account for the contribution of RSV to confounding the estimates of influenza-related admissions in young children, neither study was based on virologic confirmation of individual cases. Viral culture data were provided by a third study, which was a 25-year prospective cohort analysis of 1665 children <5 years of age enrolled in the Vanderbilt Vaccine Clinic in Nashville, TN during 1974 theough 1999. 11 Viral culture for respiratory viruses was routinely performed on specimens from all children who presented with a febrile illness, acute respiratory illness or acute otitis media. The annual rate of culture-confirmed influenza admissions was 300 to 400 per 100 000 clinic patients younger than 2 years.
These three studies gave evidence that hospital admissions for influenza-related complications among healthy US children younger than 2 years of age were similar to those among the elderly and persons with high risk conditions. They were therefore pivotal in focusing the attention of the ACIP on young children.
LIVE ATTENUATED INFLUENZA VACCINE
In addition to the above studies, the interest of the ACIP in recommending vaccination for young children was also spurred by the possible approval of a live attenuated influenza vaccine (LAIV). At the time of the mentioned studies, a trivalent inactivated influenza vaccine (TIV) was the only licensed influenza vaccine in the US. Many ACIP members felt that an influenza vaccine that could be given without a needle would be a strong stimulus for vaccinating children. On June 17, 2003, the US Food and Drug Administration approved LAIV for use in healthy people 5 to 9 years of age. 20 Therefore TIV is still the only influenza vaccine approved for children 6 to 23 months of age.
PEDIATRIC VACCINATION POLICY CONSIDERATIONS
Despite the available results, the ACIP did not proceed immediately with a recommendation to vaccinate all children younger than 2 years of age but instead took an intermediate step of “encouraging” vaccination of children <2 years of age “when feasible.” This was in recognition of the need to better address several issues, including the safety and efficacy of influenza vaccine in young children, and the logistics of expanding routine influenza vaccination to children. In exploring potential recommendations and the challenges associated with successful implementation of annual vaccination of healthy children, the ACIP worked closely with several groups, particularly the American Academy of Pediatrics and the American Academy of Family Practice. 21
VACCINE SAFETY
There are limited safety data from clinical trials of TIVs in which the total antigen contents were similar to that of contemporary vaccines and that were conducted among children 6 to 23 months of age in the US. In the available studies vaccination with TIV was generally well-tolerated but adverse events, including local reactions, fever, cough, rhinitis, irritability and febrile seizure, were reported. There were no severe adverse reactions in healthy children or those with conditions such as chronic lung or heart disease. However, there were too few children 6 to 23 months of age to detect uncommon adverse events. 22–25
VACCINE EFFICACY
The efficacy of influenza vaccine is affected by several factors, including age and immune status, the circulating strains and the antigenic match between the vaccine and the circulating influenza strains. 23 Most US studies have been too small to enable adequate assessment of vaccine efficacy in young children. A 2-year randomized, controlled trial of TIV in children 6 to 24 months of age showed that ≥89% of the children seroconverted to all three vaccine strains. 26 Vaccine efficacy was 66% against culture-confirmed influenza among the 411 children enrolled in the first year, but it was –7% among the 375 children enrolled in the second year of the study (a year during which there were insufficient numbers of influenza illnesses among study participants to adequately assess vaccine efficacy).
VACCINE SUPPLY
During the 2000 to 2001 and 2001 to 2002 influenza seasons, vaccine production and regulatory issues resulted in manufacturing delays, uneven distribution and functional shortages of influenza vaccine among some groups. These experiences emphasize the need for an adequate and reliable vaccine supply for successful implementation of influenza vaccination recommendations. 27
Influenza vaccination is currently recommended for ∼180 million people in the US (78 million in high risk groups and another 102 million health care workers, household contacts and people 50 to 64 years of age). Because ∼7 million children are in the 6- to 23-month- old age group during the influenza season, vaccinating them and their caregivers could substantially add to the demand for influenza vaccine. 2
The current status of influenza vaccine production is somewhat mixed in the US. On one hand vaccine production and coverage have grown substantially recently despite supply delays. For example between 1961 and 2002 to 2003, the estimated numbers of influenza vaccine doses for sale in the US increased from ∼20 million 28 to ∼95 million (of which ∼79 million were distributed in 2002; D O’Mara, personal communication, February 2003 ACIP meeting). On the other hand the number of companies producing TIV for the US declined from 4 in 1999 to 2 in 2002. The reliance on fewer manufacturers for influenza vaccine means risking more shortages if the remaining companies have difficulties in growing or processing vaccine strains or addressing regulatory issues.
In response to the 2000 and 2001 influenza vaccine delays, the ACIP recommended a tiered vaccination schedule to try to ensure that vaccine is made first available to priority groups early in the season. 2 Children younger than 9 years being given influenza vaccine for the first time are considered immunologically unprimed for influenza and should have two doses of vaccine at least 1 month apart. The logistics of vaccinating young children make the early availability of influenza vaccine particularly important for this age group.
EDUCATION
In 2000 the American Academy of Pediatrics surveyed its fellows and found that 30% of respondents supported recommending universal vaccination of infants >6 months of age, but 43% opposed it and 27% were neutral. The respondents said that among the important factors influencing their attitudes were the risk of serious complications of influenza, vaccine safety and the availability of a nasal spray vaccine. 29 A survey of 189 parents in Tennessee, identified the recommendation of a physician as the most important factor influencing the decision to vaccinate their child. These examples highlight the need to give health care providers and parents appropriate and comprehensive information about influenza and influenza vaccine. 29
INFLUENZA IN CHILDREN YOUNGER THAN 6 MONTHS
Influenza vaccine is not approved for use in infants younger than 6 months of age. However, influenza vaccination is recommended for women who are in their second or third trimester of pregnancy during the influenza season, 2 and there is much interest in whether vaccinating pregnant women would protect their infants. Such protection might be achieved through transfer of antibodies via the placenta 31–33 or breast milk, or by preventing direct transmission of influenza infection from mother to infant. However, the current data on this topic are limited. If maternal vaccination protects infants from influenza, increased efforts could be devoted to raising vaccination levels among pregnant women.
FUTURE CONSIDERATIONS
Currently it is not known when the ACIP will recommend vaccinating all children 6 to 23 months of age against influenza. Although the recent approval of a trivalent LAIV could stimulate interest in vaccination of children, thus far it has been approved only for healthy people 5 to 49 years of age. In the meantime the ACIP will continue to review data from ongoing studies of TIV and to work with its partners to educate health care providers and parents to find ways of successfully implementing annual influenza vaccination.
We thank Dr. Carolyn Bridges for her assistance.
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